The Chemistry of Reactivation at the Active Centres of Acetylcholinesterase and Receptor

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Abstract
Contrary to the overwhelming expectations in special papers and textbooks, the reactivation of the active centre of acetylcholinesterase, inhibited by organophosphorous compounds, with the help of so called “tailor-made-drugs”, e.g. the oximes, never could be realized in vivo. However, the concept of the tailor-made drugs gave us a thorough insight in the function of synapses. As the chemical background of the basic reactions of catalysis of the hydrolysis of acetylcholine, carbamates and organophosphates at the active centre is now investigated, the reason for the failure of the “tailor-made-drugs-concept” can be discussed. The rate limiting step in all naturally “reactivation-reactions” is the hydrolysis of the acetylated, carbamoylated and phosphorylated enzyme. Thus the acceleration of the hydrolysis of the phosphorylated enzyme proved to be the most promising way for reactivation in vitro. However, in vivo the oximes alone never proved to be successful. The only successful way in a very limited dose range is to combine the oximes with atropine and/or other anticholinergic drugs. On the other hand, drugs without oxime groups, e.g. edrophonium, with obviously no capability to reactivate the enzyme blocked by organophosphates, behave almost like the oximes. Thus another mechanism concerning a direct action on the acetylcholine receptor has to be taken into account.